The central hypothesis of the application is that specific inhibitors of HIV-i fusion with target cells, when used in combination and when properly formulated and used appropriately, could prevent the vaginal or rectal transmission of HIV-i. In Research Project II, we will focus on the critical issue of microbicide formulation and delivery. We are conscious of recent experience from large-scale trials indicating that compliance is a very significant issue in microbicide research and development today. Specifically, there are now serious concerns whether a microbicide intended for use immediately prior to sexual intercourse is a truly practical proposition;poor compliance in clinical trials may easily translate to the limited usage should any product make it to licensure. Therefore, the aim of Research Project II is to develop longlasting, coitally-independent delivery methods for entry inhibitor-based microbicides, in the form of sustained release semi-solid formulations that are applied once daily, and controlled release vaginal rings that can provide a continuous and constant supply of the active compound(s) in situ for a period of weeks/months after application of a single device. These two very different formulation strategies are deliberately being pursued within this project on account of the widely accepted consensus that a number of microbicide products will be required to meet the differing social and cultural preferences of women. There are four specific objectives within Project II: i) To develop controlled-release matrix and reservoirtype vaginal ring devices containing each of the small molecule entry inhibitors CMPD 167, BMS-C and AMD3465. 2) To develop novel controlled release vaginal rings ('rod-insert'rings) containing the peptide entry inhibitor T-124Q. 3) To develop controlled release vaginal rings containing combination entry inhibitors. 4) To develop sustained-release semi-solid formulations of the small molecule entry inhibitors CMPD 167, BMS-C, AMD34&5 and T-1249, both alone and in combination, for once-daily application. The Project Leader will be R. Karl Malcolm, Ph.D., with Mark Mitchnick, Ph.D. and A. David Woolfson, Ph.D. acting as co-investigators. The vaginal ring formulation component of the Project will be conducted at the School of Pharmacy, Queen's University Belfast, UK, while the semi-solid formulation component will be conducted at Particle Sciences Inc. PA, US. Both groups have considerable expertise in their respective formulation tasks.